Autophagy is disrupted in many disease conditions and the underlying mechanism is still unclear. Diseases such as Huntington's, Alzheimer's, cystic fibrosis (CF) and Parkinson's diseases are characterized by aggregates of mutant proteins and are often associated with weak autophagy activity. In this proposal, we focus on CF which is the most common inherited lethal disease among Caucasians, and is caused by mutations in the cftr gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Our recent studies demonstrated that macrophages from CF patients and CF mice have weak autophagy. Furthermore, we have identified specific microRNAs targeting essential autophagy molecules that are elevated in macrophages from CF patients and CF mice associated with low expression of the predicted autophagy gene targets. We therefore hypothesize that altered autophagy in macrophages of CF patients is due to the high levels of certain miRs. Weak autophagy then contributes to the chronic infection and excessive inflammation observed in the lung of CF patients, and loss of pulmonary function. Notably, our data also suggest that weak autophagy contributes to low CFTR function. This grant proposal will (a) determine the epigenetic changes and other mechanisms leading to increased expression of these specific miRNAs in CF patients and CF mice, and (b) establish that reducing the expression of these specific miRNAs will correct CFTR function, restore bacterial clearance, and alleviate excessive inflammation.